The major metabolic transformations of estradiol are believed to occur in the five membered ring. Subsequently, it was demonstrated that the aromatic ring could also undergo metabolic transformation to yield 1-hydroxy estrogens which are termed catecholestrogens. It was shown that the catecholestrogens are a major metabolic product of the metabolism of estradiol and that they are normally present in significant quantities. Following the detection of endogenous catecholestrogens in man, research efforts were directed toward the possibility that metabolism of estradiol to catecholestrogens may contribute to the actions of the hormone. Furthermore, catecholamines have been thought to mediate the responses to estrogen and emergence of catecholestrogens as a major metabolite of estrogen provide a biochemical link between the estrogens and the catecholamines. The hypothesis to be tested in the current proposal is that the catecholestrogens modify the nerve-stimulation mediated release of the adrenergic transmitter, norepinephrine, both peripherally and in the central nervous system. We propose to use the isolated, perfused cat spleen for studying the effect of the catecholestrogens on the peripheral adrenergic system. The isolated perfused cat spleen has been used as a model for examining the synthesis and release of endogenous norepinephrine and other secretory products of the adrenergic nerve terminal. The release of norepinephrine in the central nervous system will be studied using the cortical cup superperfusion technique in which a perfusion chamber is placed on the cerebral cortex. This method can be performed with minimal risk of tissue damage. These results should help to unravel the complex mode of action of estrogen.